A phase I, first-in-human clinical trial of the GDF-15 neutralizing antibody CTL-002 in subjects with advanced-stage solid tumors (ACRONYM: GDFATHER).

Abstract

TPS2658 Background: Growth and differentiation factor 15 (GDF-15) is a TGF-β superfamily member physiologically expressed mainly in placenta and linked to feto-maternal tolerance. Under pathophysiologic conditions, prevention of excessive immune cell infiltration during tissue damage and cachexia induction have been ascribed to GDF-15. A recent study [Haake et al. AACR2020; Abstract #5597] elucidated a mechanism by which GDF-15 inhibits LFA-1 activation on CD8+ T cells, thus interfering with effector T cell recruitment to tissues. Importantly, several cancer entities secrete high levels of GDF-15, correlating with poor prognosis and reduced overall survival [reviewed in Front Immunol 2020 May 19;11:951]. To block this effect the GDF-15 neutralizing antibody CTL-002 was generated. In preclinical models CTL-002 demonstrated potent effector T cell shifting into tumor tissue by neutralizing GDF-15. Methods: This is a phase 1, first-in-human (FIH), two-part, open-label clinical trial of intravenous (IV) administration of CTL-002 given as monotherapy and in combination with an anti-PD-1 antibody in subjects with advanced-stage, relapsed/refractory solid tumors who relapsed post or were refractory to a prior anti-PD-1/PD-L1 therapy. Eligible subjects have exhausted all available approved standard treatments. Further key eligibility criteria include having received at least one prior anti-PD1/-PD-L1 treatment and having relapsed on or after it or having been refractory to it, and presenting with a biopsy-accessible tumor for serial biopsy taking. The trial is termed GDFATHER, for “GDF-15 Antibody-mediaTed Effector cell Relocation”. Main endpoints are safety of CTL-002 monotherapy and CTL-002 combination with an anti-PD-1 antibody, pharmacokinetics, pharmacodynamics (e.g. degree of GDF-15 neutralization achieved and change in immune-cell number and composition in the tumor tissue) as well as preliminary clinical efficacy (tumor mass reduction; anticachexia effect) In part A of the trial (dose escalation) up to 24 subjects will receive escalating doses of CTL-002 IV (0.3 – 20 mg/kg) in a „mono-followed-by-combination“-design with CTL-002 given as monotherapy and followed by combination with an anti-PD-1 checkpoint inhibitor. In part B (expansion) up to 5 cohorts with up to 25 subjects per cohort with defined tumor entities expected to be GDF-15 dependent will be treated to determine the recommended phase 2 dose (RP2D) and further evaluate safety and preliminary efficacy of CTL-002 monotherapy and the combination. The study was initiated in December 2020 and enrolled the first patient on Dec 09, 2020. Cohort 1 has been completed without DLT and enrollment for cohort 2 began in February 2021. Clinical trial information: NCT04725474.

Distinct single-cell immune ecosystems distinguish true and de novo HBV-related hepatocellular carcinoma recurrences

“…Of note, the GDF15 neutralising antibody CTL-002 is clinically available and was recently tested in a first-in-human phase I clinical trial in patients with advanced solid malignancies (NCT04725474). 55 Study results showed that CTL-002 in combination with PD-1 blockade is safe and could induce objective durable responses in heavily pretreated, anti-PD-1/PD-L1-experienced relapsed cancer patients 56…”

The Cytokine Growth Differentiation Factor-15 and Skeletal Muscle Health: Portrait of an Emerging Widely Applicable Disease Biomarker

“…In the NCT04068896 phase 1/2 dose-finding study with a GFRAL antagonist monoclonal antibody in combination therapy, blocking of GFD-15 signaling is evaluated in subjects with advanced solid tumors and pancreatic cancer. In the GDFATHER trial (NCT04725474), the possible anti-cachexia effects of a monoclonal anti-GDF-15 antibody in monotherapy or in combination with a checkpoint inhibitor is being evaluated in patients with advanced cancers [ 125 ].…”

Distinct Single-cell Immune Ecosystems Distinguish True and De Novo HBV-related Hepatocellular Carcinoma Recurrences

“…These data suggest that treatments targeting GDF15 + malignant cells or inducing neoantigen release, or helping neoantigen presentation might be more rational for truly recurrent HCC patients, for example, GDF15 blockade with or without the combination of DC vaccine or adoptive T cell transfer (Melief et al, 2015; Mardiana et al, 2019). The GDF15 neutralizing antibody CTL-002 is clinically available and is currently being tested in a phase I, first-in-human clinical trial in patients with advanced-stage solid malignancy (NCT04725474) (Melero et al, 2021).…”